Reexpression of p8 Contributes to Tumorigenic Properties of Pituitary Cells and Appears in a Subset of Prolactinomas in Transgenic Mice that Hypersecrete Luteinizing Hormone

Abstract

Targeted overexpression of LH in transgenic mice causes hyperproliferation of Pit-1-positive pituitary cells and development of functional adenomas. To characterize gene expression changes associated with pituitary tumorigenesis, we performed microarray studies using Affymetrix GeneChips comparing expression profiles from pituitary tumors in LH-overexpressing mice to wild-type control pituitaries. We identified a number of candidate genes with altered expression in pituitary tumors. One of these, p8 (candidate of metastasis-1), encodes a native high-mobility group-like transcription factor previously shown to be necessary for ras-mediated transformation of mouse embryonic fibroblasts and also implicated in breast cancer progression. Herein, we show that expression of p8, normally quiescent in adult pituitary, localizes to tumor foci containing lactotropes, suggesting a linkage with their transformation. To further establish the functional significance of p8 in pituitary tumorigenesis, we constructed several clonal cell lines with reduced expression of p8 from a parent GH3 somatolactotrope cell line. These clonal derivates, along with the parent cell line, were tested for tumorigenicity by injection into athymic mice. When compared with wild-type GH3 with higher levels of p8, GH3 cells with reduced expression of p8 displayed attenuated tumor development or failed to develop tumors at all. Similar results were obtained with gonadotrope-derived cell lines that displayed reduced expression of p8. Together, these data suggest that maintenance of the transformed phenotype of pituitary GH3 cells requires expression of p8 and that it may play a similar role when reexpressed in a subset of lactotropes that form prolactinomas in vivo.

Gene Expression Analysis in HBV Transgenic Mouse Liver: A Model to Study Early Events Related to Hepatocarcinogenesis

“…In particular, a large number of upregulated genes were involved in the modulation of immunological functions, suggesting that the accumulation in the hepatocytes of viral proteins yielded cellular damage followed by an immune response (23,27,29). In addition, several upregulated transcripts have already been correlated to cellular dysplasia and tumor malignancy in different types of cancer (48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59). The microarray data showed the upregulation of NuprI, a transcription factor whose overexpression is inversely correlated with apoptosis in pancreatic cancer (60), and the downregulation of the proapoptotic gene Bnip3 (61,62).…”

Developmentally regulated synthesis of p8, a stress-associated transcription cofactor, in diapause-destined embryos of Artemia franciscana

“…For example, p8 may buttress defense against cell injury (Vasseur et al 2004;Malicet et al 2006b) and promote growth (Vasseur et al 1999a;Garcia-Montero et al 2001;Päth, et al 2006;Malicet et al 2006b). In contrast, p8 also inhibits cell growth and suppresses tumors (Bratland et al 2000;Vasseur et al 2002aVasseur et al , 2002bZinke et al 2002;Malicet et al 2003;Jiang et al 2005Jiang et al , 2006 while maintaining tumor phenotype by a mechanism perhaps different from growth promotion per se (Ree et al 1999;Su et al 2001;Vasseur et al 2002b;Mohammad et al 2004). p8 is both proapoptotic (Vasseur et al 2002a;Carracedo et al 2006;Plant et al 2006) and antiapoptotic (Su et al 2001;Giroux et al 2006), with inhibition thought to depend on interaction with prothymosin ␣ (Malicet et al 2006a).…”

Glucose-dependent expansion of pancreatic β-cells by the protein p8 in vitro and in vivo

“…For example, p8 expression levels in clonal sublines of rat GH3 somatolactotrope pituitary cells positively correlate with tumor size in a nude mice model (26). Consistently, MEF from p8 Ϫ/Ϫ mice transformed with mutated ras V12 protein and EA1 oncogene, as well as p8-negative human MCF7 breast cancer cells and p8 anti-sense-treated mouse L␤T2 gonadotrope pituitary cells, failed to form colonies in vitro or tumors in vivo (4,26,41). Because of these observations, p8 was suggested to play a role in tumor development.…”